Regulation of immunoglobulin A (IgA) synthesis is multifactorial, e.g., T cells, dendritic cells, and cytokines regulate isotype switching to IgA, although the exact mechanisms by which they control isotype switching are unknown. IgA is the predominant immunoglobulin isotype in mucosal secretions, tears, saliva and the upper respiratory tract and provides the first line of defense against many pathogens, functioning in agglutination and neutralization of bacteria, viruses, and toxins. IgA accounts for 70-90% of all immunoglobulins in the gut-associated lymphoid tissue (GALT) and IgA production by B cells is one of the main mechanisms of defense in the GALT (Brandtzaeg et al., 1989). The primary lymphoid organs of the GALT are the Peyer's Patches (PP) and associated areas of the small intestine, but tonsils, adenoids and appendix are also considered to be part of the GALT (Brandtzaeg et al., 1989; Delacroix et al., 1985).
Some of the cytokines and costimulators that have been identified which regulate expression of IgA include IL-I0, IL-2, vasoactive intestinal peptide (VIP), and transforming growth factor beta (TGF-β). TGF-β requires a well-documented switch factor for IgA (Coffman et al., 1989; Fayette et al., 1997). Supporting evidence for the effect of TGF-β on switch differentiation is provided by TGF-β responsive elements being identified in the regulatory regions of several CH genes (Lin et al., 1992). Under certain conditions, TGF-β requires dual B cell stimulation (via CD40 and anti-IgM) to significantly enhance IgA switching (McIntyre et al., 1995). The second activation signal through the B cell receptor may make the B cells more receptive to TGF-β signaling. Alternatively, since TGF-β has dramatic negative effects on both B and T cell proliferation, the second signal might be necessary to maintain the cell or drive the cell through the cell cycle (Kehrl et al.; 1986, Kehrl et al., 1991; Moses et al., 1990).
There is much evidence suggesting that unidentified regulators of IgA exist, particularly in the environment of the GALT. First, because TGF-β is ubiquitously found in lymphoid tissues, one would predict that IgA isotype switching would also be widespread in all lymphoid tissues. However, IgA switching predominantly occurs in the PPs (Erhardt et al., 1996). Secondly, TGF-β at optimal concentrations for cell survival induces only a small fraction of sIgM+ B cells to undergo IgA switch differentiation. In particular, in cattle, very few regulators of IgA B cell differentiation are known. B cells stimulated via CD40 and anti-IgM in the presence of TGF-β and IL-2 have enhanced production of IgA in cattle (Estes et al., 1998). However, other known IgA regulators for mice and/or humans, including VIP, IL-5, IL-6 and IL-I0, have been tested in cattle, but do not induce IgA production from B cells.
Thus, what is needed is the identification of regulator(s) of IgA+ B cell differentiation, e.g., regulators that exist in the microenvironment of the gut.